The overall objective of this proposal is to focus on a major yet poorly understood component of neural control of microvascular smooth muscle, namely, the distribution and function of postjunctional alpha 1 and alpha 2 adrenoreceptor subtypes within the microcirculation. Identification of both receptor types has only been made for large arteries and veins studied in vitro. In recent preliminary studies utilizing intravital microscopy of rat skeletal muscle we have succeeded in identifying both subtypes on smooth muscle of microvessels. While both receptors mediate contraction, our data suggest the new concept that alpha 1 receptors may dominate large arteriolar constriction, whereas alpha 2 receptors dominate terminal arteriolar constriction. Capacitance venules appear to possess both receptors. In clear distinction to alpha 1 receptors, alpha 2 receptor-mediated contraction may be particularly sensitive to changes in tissue temperature and pH well within the physiological range. Thus, three novel hypotheses will be examined: (1) The distribution and density of smooth muscle alpha 1 and alpha 2 adrenoceptors exhibit considerable heterogenity for different microvascular segments. (2) Contraction mediated by alpha 2 receptor subtypes is differentially sensitive to the local tissue environment. (3) The heterogenity of receptor distribution and sensitivity to tissue conditions confers distinct regulatory features on different microvascular segments, i.e., alpha receptor subtypes subserve distinct physiological functions. Intravital microscopy of the skeletal muscle (cremaster) microcirculation will be used to measure diameter and flow of large arterioles, terminal arterioles and capacitance venules. Aim I will quantify the pharmacological characteristics (agonist and antagonist dissociation constants, receptor occupancy) of alpha 1 and alpha 2 receptors. Aim II will examine the effect of changes in tissue temperature and pH on alpha adrenoceptor-mediated contraction. Aim III will determine the distribution of pre- and postjunctional alpha receptors across the microvasculature using functional and anatomical (quantitative in vitro autoradiography) techniques. Aim IV will examine whether alpha receptor subtypes subserve distinct physiological roles in the neural and humoral control of the microcirculation. The results to be obtained will provide a better understanding of neural regulation of the peripheral circulation, and may lead to new insights concerning the pathophysiology and treatment of peripheral vascular disorders.